GB982922A - New í¸-11ª‡-hydroxy-steroids and process for their manufacture - Google Patents

Abstract

The invention comprises (1) a process for the preparation of D 1 - 3 - oxo - 11a - hydroxy - steroids, wherein 1,11a - oxido - 3 - oxo - steroids are treated with a hydrolysing agent; (2) D 1 - 3,20 - dioxo - 11a - hydroxy - 5b - pregnene; (3) D 1,5 - 3 - oxo - 11a - hydroxy - steroids; (4) 2,3 - seco - D 1 - 11a - hydroxy - pregnene - 3 - acids acids and their 3-esters; and (5) the 1,11-lactone of the 3-methyl ester of 2,3-seco-2-nor-11a - hydroxy - 20 - oxo - 5a - pregnane - 1,3 - diacid. Process (1) may be effected, for example, with acids, and the starting material may contain a group in the 3-position which under the action of the hydrolysing agent forms a 3-keto group, for example a 3-ketal group, the D 5-double bond remaining intact in 1,11a -oxido compounds. Alternatively, the hydrolysing agent may be a basic material. D 1,5-3-keto-11a -hydroxy products may be isomerized to the corresponding D 1,4-3-ketones. Compounds (4) are formed concomitantly with D 1-3-oxo-11a -hydroxy -steroids when 1b ,11a -oxido-steroids (as opposed to the 1a -epimers) especially those containing a 3-ketal group, are treated with acids. If sulphuric acid in methanol is used a methyl ester is formed, while with dilute acetic acid, a mixture of sodium acetate and glacial acetic acid, or p-toluene sulphonic acid in acetone, the glycol ester is obtained from the 3-ketals. The glycol ester of 2,3-seco-D 1-11a -hydroxy - 20 - oxo - 5a - pregnene - 3 - acid on hydrolysis gives the free acid and this with diazomethane gives the methyl ester. Ozonization of this and subsequent oxidation gives compound (5). On treatment with concentrated sulphuric acid the 2,3-seco compounds partly re-cyclize to 1-dehydro-3-oxo-steroids. If 1,11a -oxido-steroids having no free or protected 3-keto group are treated with acidic agents, mainly mono-acylates of the corresponding 1,11-diols are obtained. Use of hydrohalic acids in hydroxylic solvents here yields 1 - halogeno - 11a - hydroxy compounds, while acyl halides give 1 - halogeno - 11a - acyloxy-acyl halides give 1-halogeno-11a -acyloxy-steroids; and in a medium free from hydroxyl groups the main products are derivatives of D 9(11)-1-hydroxy-steroids. Starting materials for process (1) may be steroids of the cholestane, cholane, coprostane, spirostane, furostane, cardanolide, pregnane or androstane (including 19-norandrostane) series and may contain further substituents, such as esterified or etherified hydroxyl groups, free or ketalized oxo groups which may be hydrolysed during the process), free, esterified or lactonized carboxyl groups, alkyl groups or halogen atoms in the ring or 17-side chain. They may also contain double bonds, e.g. D 5. Examples are given, and a list of esterifying carboxylic and sulphonic acids and etherifying alcohols is also provided. Also described are the following processes: (1) the 18,20-lactone of D 1,5-3-oxo-11a ,20b -dihydroxy-pregnadiene -18-acid is isomerized to the D 1,4-3-ketone, the tosylate of this is treated with a base to give the 11b ,18-lactone of D 1,4-3-oxo-11b ,20b -dihydroxypregnadiene - 18 - acid, the 20 - hydroxyl group in the product is oxidized to a 20-keto group, an acyloxy group is introduced into the 21-position, the 20-oxo group is ketalized, the 3-oxo group is reduced and the 18-oxo group converted into an 18,11-cyclosemi-acetal by reaction with lithium aluminium hydride, the product is oxidized by the Oppenauer method, and the 20-ketal group is hydrolysed, to give 1-dehydro-aldosterone; and (2) the D 1-double bond of the 18,20-lactones of D 1,5-3-oxo-11a ,20 - dihydroxy - steroid - 18 - acids is selectively reduced and the products isomerized, to give the 18,20 lactones of D 4-3-oxo-11,20-dihydroxy-pregnene -18-acids, and these are converted into the 11b ,18-lactones of D 4-3,20-dioxo-11b -hydroxy-pregnene -18-acids by the method described above. D 5 - 3,20 - dioxo - 1a ,11a - oxido - pregnene is formed as a by-product when D 5-3,20-bisethylene - dioxy - 1a ,11a - oxido - pregnene is treated with p-toluenesulphonic acid in aqueous acetone. When the same starting material is treated with 80% acetic acid, the initial crude product is a mixture of D 5-3-ethylenedioxy-1a ,11a -oxido-20-oxo -pregnene and the above-mentioned product. The glycol ester of 2,3-seco 11a -hydroxy-20-oxo-5a -pregnene-3 -acid is obtained when the corresponding D 1-compound is hydrogenated.